Crosslinked polyalkyleneimine hydrogels with tunable degradation rates

• US 8,846,022 B2
• Filed: 10/21/2010
• Issued: 09/30/2014
• Est. Priority Date: 02/13/2008
• Status: Active Grant

• Current Assignee: HyperBranch Medical Technology, Inc. (Stryker Corporation)
• Original Assignee: HyperBranch Medical Technology, Inc. (Stryker Corporation)
• Inventors: Carnahan, Michael A., Butlin, Jared Daniel Goodnow
• Primary Examiner(s): Godenschwager, Peter F
• Assistant Examiner(s): KARST, DAVID THOMAS
• Application Number:
  US12/909,611
• Publication Number:
  US 20110044932A1
• Time in Patent Office: 1,440 Days
• Field of Search: 523/118
• US Class Current: 424/78.36
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: C08G 65/326 containing sulfur
• CPC Class Codes: C08G 65/33337 cyclic
• CPC Class Codes: C08G 65/337 containing other elements organic compounds containing halogens only as halides of a carboxyl group C08G65/332
• CPC Class Codes: C08K 5/0025 Crosslinking or vulcanising agents; including accelerators
• CPC Class Codes: C08K 5/3415 Five-membered rings
• CPC Class Codes: C08L 101/02 characterised by the presence of specified groups , e.g. terminal or pendant functional groups
• CPC Class Codes: C08L 2203/02 for biomedical use
• CPC Class Codes: C08L 2666/20 Macromolecular compounds having nitrogen in the main chain according to C08L75/00 - C08L79/00; Derivatives thereof
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: C08L 77/04 Polyamides derived from alpha-amino carboxylic acids C08L77/10 takes precedence
• CPC Class Codes: C08L 79/02 Polyamines

Abstract

One aspect of the present invention relates to methods of sealing a wound or tissue plane or filling a void space, or securing meshes, films or other devices within the body. In certain embodiments, the wound is an ophthalmic, pleural or dural wound, or a hernia repair mesh. Remarkably, disclosed herein is the discovery that the use of certain crosslinkers in combination with polyalkyleneimines at specific concentrations can result in hydrogels with tunable degradation properties.

Claims

1. A method of sealing a wound of a patient, comprising the steps of:

combining effective amounts of an activated polyethylene glycol diacid derivative and a covalent crosslinking agent to form a polymeric composition; and

applying said polymeric composition to a wound of a patient;

wherein the covalent crosslinking agent is polyethyleneimine having a weight average molecular weight of about 400 to about 2000 Daltons;

the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is within a range of about 0.5;

1 to about 1.5;

1; and

the activated polyethylene glycol diacid derivative is represented by formula I;

2. The method of claim 1, wherein the polyethyleneimine has a weight average molecular weight of about 2000 Daltons.

3. The method of claim 1, wherein m is 8.

4. The method of claim 1, wherein the activated polyethylene glycol diacid derivative is PEG_n-(SSeb)₂;

wherein PEG is polyethylene glycol;

n represents the number average molecular weight of the PEG;

n is about 3350; and

SSeb is

5. The method of claim 1, wherein the polymeric composition comprises about 15 weight percent of the polyethylene glycol diacid derivative and the polyethyleneimine.

6. The method of claim 1, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the crosslinking agent is in the range from about 0.75:

1 to about 1.3;

1.

7. The method of claim 1, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 0.5:

1.

8. The method of claim 1, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 0.75:

1.

9. The method of claim 1, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 1.15:

1.

10. A method of augmenting soft tissue or filling a void of a patient, comprising the steps of:

combining effective amounts of an activated polyethylene glycol diacid derivative and a covalent crosslinking agent to form a polymeric composition; and

applying said polymeric composition to soft tissue or a void of a patient;

wherein the covalent crosslinking agent is polyethyleneimine having a weight average molecular weight of about 400 to about 2000 Daltons;

the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is within a range of about 0.5;

1 to about 1.5;

1; and

the activated polyethylene glycol diacid derivative is represented by formula I;

11. The method of claim 10, wherein the polyethyleneimine has a weight average molecular weight of about 2000 Daltons.

12. The method of claim 10, wherein m is 8.

13. The method of claim 10, wherein the activated polyethylene glycol diacid derivative is PEG_n-(SSeb)₂;

wherein PEG is polyethylene glycol;

n represents the number average molecular weight of the PEG;

n is about 3350; and

SSeb is

14. The method of claim 10, wherein the polymeric composition comprises about 15 weight percent of the polyethylene glycol diacid derivative and the polyethyleneimine.

15. The method of claim 10, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the crosslinking agent is in the range from about 0.75:

1 to about 1.3;

1.

16. The method of claim 10, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 0.5:

1.

17. The method of claim 10, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 0.75:

1.

18. The method of claim 10, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 1.15:

1.

19. A method of adhering tissues of a patient, comprising the steps of:

combining effective amounts of an activated polyethylene glycol diacid derivative and a covalent crosslinking agent to form a polymeric composition; and

applying said polymeric composition to a first tissue of a patient to form a modified tissue; and

contacting said modified tissue with a second tissue of the patient;

wherein the covalent crosslinking agent is polyethyleneimine having a weight average molecular weight of about 400 to about 2000 Daltons;

the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is within a range of about 0.5;

1 to about 1.5;

1; and

the activated polyethylene glycol diacid derivative is represented by formula I;

20. The method of claim 19, wherein the polyethyleneimine has a weight average molecular weight of about 2000 Daltons.

21. The method of claim 19, wherein m is 8.

22. The method of claim 19, wherein the activated polyethylene glycol diacid derivative is PEG_n-(SSeb)₂;

wherein PEG is polyethylene glycol;

n represents the number average molecular weight of the PEG;

n is about 3350; and

SSeb is

23. The method of claim 19, wherein the polymeric composition comprises about 15 weight percent of the polyethylene glycol diacid derivative and the polyethyleneimine.

24. The method of claim 19, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the crosslinking agent is in the range from about 0.75:

1 to about 1.3;

1.

25. The method of claim 19, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 0.5:

1.

26. The method of claim 19, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 0.75:

1.

27. The method of claim 19, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 1.15:

1.

28. A method of securing a prosthetic material to a tissue of a patient, comprising the steps of:

combining effective amounts of an activated polyethylene glycol diacid derivative and a covalent crosslinking agent to form a polymeric composition; and

applying said polymeric composition to the prosthetic material, thereby forming a modified prosthetic material; and

contacting the modified prosthetic material to the tissue of the patient, thereby securing the modified prosthetic material to the tissue of the patient;

wherein the covalent crosslinking agent is polyethyleneimine having a weight average molecular weight of about 400 to about 2000 Daltons;

the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is within a range of about 0.5;

1 to about 1.5;

1; and

the activated polyethylene glycol diacid derivative is represented by formula I;

29. The method of claim 28, wherein the polyethyleneimine has a weight average molecular weight of about 2000 Daltons.

30. The method of claim 28, wherein m is 8.

31. The method of claim 28, wherein the activated polyethylene glycol diacid derivative is PEG_n-(SSeb)₂;

wherein PEG is polyethylene glycol;

n represents the number average molecular weight of the PEG;

n is about 3350; and

SSeb is

32. The method of claim 28, wherein the polymeric composition comprises about 15 weight percent of the polyethylene glycol diacid derivative and the polyethyleneimine.

33. The method of claim 28, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the crosslinking agent is in the range from about 0.75:

1 to about 1.3;

1.

34. The method of claim 28, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 0.5:

1.

35. The method of claim 28, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 0.75:

1.

36. The method of claim 28, wherein the molar ratio of activated esters on the polyethylene glycol diacid derivative to primary amines on the polyethyleneimine is about 1.15:

1.